N-acetylcysteine (NAC) is available in health food stores and widely used as an antioxidant. NAC is the acetylated form of L-cysteine, a rate-limiting factor in synthesis of glutathione (GSH), tripeptide made up of cysteine, glutamic acid, and glycine, which plays key roles in maintenance of a reducing intracellular environment, regulation of the mitochondrial transmembrane potential, and production of reactive oxygen intermediates (ROI). The pathogenesis of systemic lupus erythematosus (SLE), a potentially fatal autoimmune disease of unknown etiology, is characterized by abnormal T-cell activation and death, processes which are crucially dependent on the controlled production of ROI and of ATP in the mitochondria. We found that lupus T cells exhibit persistent mitochondrial hyperpolarization (MHP), increased mitochondrial biogenesis, and increased ROI production as well as depletion of ATP and GSH which decrease activation-induced apoptosis and instead predispose T cells for necrosis, thus activating B cells and dendritic cells and stimulating inflammation in SLE. GSH is also depleted in lymphocytes of lupus-prone mice and NAC and other antioxidants reduce autoantibody production, prevent the development of glomerulonephritis, and prolong the survival of lupus-prone mice. Current therapy of SLE patients is based on the use of prednisone and immunosuppressants which have limited efficacy and serious side-effects. In a recent European study, NAC, added to prednisone and azathioprine, resulted in clinical improvement of patients with idiopathic pulmonary fibrosis. NAC has been shown to improve fatigue and muscle endurance, a major complaint in patients with SLE. NAC can effectively raise intracellular GSH of lymphocytes both in vitro and in vivo. Therefore, the specific aims of this double-blind placebo-controlled dose-comparison study will test the hypothesis that treatment with NAC will result in elevation of intracellular GSH and reverse the MHP, ATP depletion and predisposition of lupus T cells to necrosis and, consequently, diminish activation of B cells and dendritic cells, production of auto-antibodies, and disease activity in patients with SLE. Under Specific Aim 1, we will determine the daily oral dose of NAC that is well tolerated and capable of normalizing or moderating the depletion of GSH and MHP in T cells of patients with SLE over a period of 3 months. Under Specific Aim 2, we will determine the impact of an optimal NAC dose on disease activity and prednisone use in patients with SLE over a period of 12 months. As clinical outcomes, we will assess lupus disease activity by SELENA/SLEDAI and BILAG, liver and bone marrow function, overall fatigue, and muscle endurance. As immunological outcomes, we will assess intracellular GSH content, MHP, ATP, Ca2+ fluxing, predisposition to necrosis and mitochondrial gene expression signature of T cells, activation of B cells, and production of NO and interferon-a by monocytes and dendritic cells. The results of this study will establish whether administration of NAC can restore or at least significantly modulate low GSH and dysfunction of T cells, activation of B cells and dendritic cells, and thus improve the disease manifestations in SLE. PUBLIC HEALTH REVELANCE: Systemic lupus erythematosus (SLE) is a chronic inflammatory disease which often has debilitating and potentially life-threatening consequences. The cause of SLE is unknown and current therapies lack specificity and carry significant side effects. Existing data in the literature provide evidence that a natural antioxidant, glutathione, is depleted in T cells of patients with SLE which may be a key factor underlying abnormal activation and predisposition of T lymphocytes to pro-inflammatory cell death via necrosis. Administration of N-acetylcysteine (NAC), that serves as a precursor of GSH, improves the clinical outcome of murine lupus, and limits the toxicity of pro-oxidant/immunosuppressant medications (4) commonly used in patients with SLE. NAC is widely available in health food stores and large doses (up to 8 g/day) can be safely administered to humans(1). In a one-year study of patients with inflammatory lung disease treated with prednisone and azathioprine, addition of NAC (1.8g/day) diminished disease severity and reduced drug toxicity in comparison to placebo. Moreover, oral NAC has been found to improve muscle fatigue (5-7) which is reported to be the most disabling symptom in 53% of patients with SLE (8). Thus, establishing a dose ranging between 1.8-7.2 g/day that is well-tolerated and capable of raising intracellular GSH in lupus patients and determining its immunological and therapeutic impact in SLE appear to be well justified.